Summary Public Assessment Report Generics Apixaban Denk 2.5 mg and 5 mg film-coated tablets - MT/H/0438/001-002/DC Apixaban Date: 15/02/2021
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CMDh/305/2013
March 2018, Rev.02
Summary Public Assessment Report
Generics
Apixaban Denk 2.5 mg and 5 mg film-coated tablets
MT/H/0438/001-002/DC
Apixaban
Date: 15/02/2021
Summary & Scientific PAR – Generics 1/13Summary Public Assessment Report
Generics
Apixaban Denk 2.5 mg, Apixaban Denk 5 mg film-coated tablets
This is a summary of the public assessment report (PAR) for Apixaban Denk. It explains how
Apixaban Denk was assessed and its authorisation recommended as well as its conditions of use. It is
not intended to provide practical advice on how to use Apixaban Denk.
For practical information about using Apixaban Denk patients should read the package leaflet or
contact their doctor or pharmacist.
What is Apixaban Denk and what is it used for?
Apixaban Denk is a ‘generic medicine’. This means that Apixaban Denk is similar to a ‘reference
medicine’ already authorised in the European Union (EU) called Eliquis®.
.
Apixaban Denk 2.5 mg is used in adults:
- to prevent blood clots (deep vein thrombosis [DVT]) from forming after hip or knee
replacement operations. After an operation to the hip or knee you may be at a higher risk of
developing blood clots in your leg veins. This can cause the legs to swell, with or without
pain. If a blood clot travels from your leg to your lungs, it can block blood flow causing
breathlessness, with or without chest pain. This condition (pulmonary embolism) can be life-
threatening and requires immediate medical attention.
Apixaban Denk 2.5 mg and 5 mg is used in adults:
- to prevent a blood clot from forming in the heart in patients with an irregular heart beat (atrial
fibrillation) and at least one additional risk factor. Blood clots may break off and travel to the
brain and lead to a stroke or to other organs and prevent normal blood flow to that organ (also
known as a systemic embolism). A stroke can be life-threatening and requires immediate
medical attention.
- to treat blood clots in the veins of your legs (deep vein thrombosis) and in the blood vessels of
your lungs (pulmonary embolism), and to prevent blood clots from re-occurring in the blood
vessels of your legs and/or lungs.
How does Apixaban Denk work?
Apixaban Denk helps to prevent blood clots from forming by blocking Factor Xa, which is an
important component of blood clotting.
How is Apixaban Denk used?
The pharmaceutical form of Apixaban Denk is film-coated tablets and the route of administration is
oral administration.
Please read section 3 of the PL for detailed information on dosing recommendations, the route of
administration, and the duration of treatment.
To prevent blood clots from forming after hip or knee replacement operations
The recommended dose is one tablet of Apixaban Denk 2.5 mg twice a day.
For example, one in the morning and one in the evening.
You should take the first tablet 12 to 24 hours after your operation.
Summary & Scientific PAR – Generics 2/13If you have had a major hip operation you will usually take the tablets for 32 to 38 days.
If you have had a major knee operation you will usually take the tablets for 10 to 14 days.
To prevent a blood clot from forming in the heart in patients with an irregular heart beat and at least
one additional risk factor
The recommended dose is one tablet of Apixaban Denk 5 mg twice a day.
The recommended dose is one tablet of Apixaban Denk 2.5 mg twice a day if:
- you have severely reduced kidney function
- two or more of the following apply to you:
- your blood test results suggest poor kidney function (value of serum creatinine is
1.5 mg/dl (133 micromole/l) or greater)
- you are 80 years old or older
- your weight is 60 kg or lower.
The recommended dose is one tablet twice a day, for example, one in the morning and one in the
evening. Your doctor will decide how long you must continue treatment for.
To treat blood clots in the veins of your legs and blood clots in the blood vessels of your lungs
The recommended dose is two tablets of Apixaban Denk 5 mg twice a day for the first 7 days, for
example, two in the morning and two in the evening.
After 7 days the recommended dose is one tablet of Apixaban Denk 5 mg twice a day, for example,
one in the morning and one in the evening.
For preventing blood clots from re-occurring following completion of 6 months of treatment
The recommended dose is one tablet of Apixaban Denk 2.5 mg twice a day for example, one in the
morning and one in the evening.
Your doctor will decide how long you must continue treatment for.
Your doctor might change your anticoagulant treatment as follows:
- Changing from Apixaban Denk to anticoagulant medicines
Stop taking Apixaban Denk. Start treatment with the anticoagulant medicines (for example
heparin) at the time you would have taken the next tablet.
- Changing from anticoagulant medicines to Apixaban Denk
Stop taking the anticoagulant medicines. Start treatment with Apixaban Denk at the time you
would have had the next dose of anticoagulant medicine, then continue as normal.
- Changing from treatment with anticoagulant containing vitamin K antagonist (e.g. warfarin) to
Apixaban Denk
Stop taking the medicine containing a vitamin K antagonist. Your doctor needs to do blood-
measurements and instruct you when to start taking Apixaban Denk.
- Changing from Apixaban Denk to anticoagulant treatment containing vitamin K antagonist
(e.g. warfarin)
If your doctor tells you that you have to start taking the medicine containing a vitamin K
antagonist, continue to take Apixaban Denk for at least 2 days after your first dose of the
medicine containing a vitamin K antagonist. Your doctor needs to do blood-measurements and
instruct you when to stop taking Apixaban Denk.
Patients undergoing cardioversion
If your abnormal heartbeat needs to be restored to normal by a procedure called cardioversion, take
Apixaban Denk at the times your doctor tells you, to prevent blood clots in blood vessels in your brain
and other blood vessels in your body.
Summary & Scientific PAR – Generics 3/13If you take more Apixaban Denk than you should
Tell your doctor immediately if you have taken more than the prescribed dose of Apixaban Denk.
Take the medicine pack with you, even if there are no tablets left.
If you take more Apixaban Denk than recommended, you may have an increased risk of bleeding. If
bleeding occurs, surgery, blood transfusions or other treatments that may reverse anti-factor Xa
activity may be required.
If you forget to take Apixaban Denk
Take the dose as soon as you remember and
- take the next dose of Apixaban Denk at the usual time
- then continue as normal.
If you are not sure what to do or have missed more than one dose, ask your doctor or pharmacist.
If you stop taking Apixaban Denk
Do not stop taking Apixaban Denk without talking to your doctor first, because the risk of developing
a blood clot could be higher if you stop treatment too early.
The medicine can only be obtained with a prescription.
What benefits of Apixaban Denk have been shown in studies?
Because Apixaban Denk is a generic medicine, studies in patients have been limited to tests to
determine that it is bioequivalent to the reference medicine, Eliquis®. Two medicines are
bioequivalent when they produce the same levels of the active substance in the body.
The company provided data from the published literature on apixaban.
What are the possible side effects of Apixaban Denk?
Because Apixaban Denk is a generic medicine and is bioequivalent to the reference medicine, its
benefits and possible side effects are taken as being the same as the reference medicine.
For the full list of restrictions, see the package leaflet.
Why is Apixaban Denk approved?
It was concluded that, in accordance with EU requirements, Apixaban Denk has been shown to have
comparable quality and to be bioequivalent to Eliquis®. Therefore, the Medicines Authority decided
that, as for reference medicine called Eliquis®, the benefits are greater than its risk and recommended
that it can be approved for use.
Apixaban Denk has been authorised with the condition to perform further studies and/or to provide
additional measures to minimise the risk. See section below “What measures are being taken to ensure
the safe and effective use of Apixaban Denk?”
What measures are being taken to ensure the safe and effective use of Apixaban Denk?
A risk management plan has been developed to ensure that Apixaban Denk is used as safely as
possible. Based on this plan, safety information has been included in the summary of product
characteristics and the package leaflet for Apixaban Denk including the appropriate precautions to be
followed by healthcare professionals and patients.
Known side effects are continuously monitored. Furthermore new safety signals reported by
patients/healthcare professionals will be monitored/reviewed continuously as well.
Summary & Scientific PAR – Generics 4/13Additional risk minimisation measures:
-Prescriber Guide
-Patient Alert Card
Other information about Apixaban Denk
The marketing authorisation for Apixaban Denk was granted on 15/02/2021.
The full PAR for Apixaban Denk can be found on the website . For more
information about treatment with Apixaban Denk read the package leaflet (link) or contact your doctor
or pharmacist.
This summary was last updated in 02-2021.
Summary & Scientific PAR – Generics 5/13CMDh/223/2005
February 2014
Public Assessment Report
Scientific discussion
Apixaban Denk 2.5 mg and 5 mg film-coated tablets
Apixaban
MT/H/0438/001-002/DC
Date: 05/03/2021
This module reflects the scientific discussion for the approval of Apixaban Denk. The procedure
was finalised at 08/02/2021. For information on changes after this date please refer to the module
‘Update’.
Summary & Scientific PAR – Generics 6/13I. INTRODUCTION
Based on the review of the quality, safety and efficacy data, the Member States have granted a
marketing authorisation for Apixaban Denk 2.5 mg, 5 mg film-coated tablets, from Denk Pharma
GmbH & Co. KG.
Apixaban Denk 2.5 mg film-coated tablets is indicated for:
- Prevention of venous thromboembolic events (VTE) in adult patients who have undergone
elective hip or knee replacement surgery.
Apixaban Denk 2.5 mg and 5 mg film-coated tablets are indicated for:
- Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation
(NVAF), with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA);
age ≥ 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II).
- Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of
recurrent DVT and PE in adults (see section 4.4 for haemodynamically unstable PE patients).
A comprehensive description of the indications and posology is given in the SmPC.
The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC.
II. QUALITY ASPECTS
II.1 Introduction
Pharmaceutical form
Apixaban Denk 2.5 mg film-coated tablets are yellow, round biconvex approximately 6 mm diameter,
3 mm thickness film-coated tablets.
Apixaban Denk 5 mg film-coated tablets are pink, oval-shaped, biconvex approximately 10 mm
length, 5.4 mm width, 4 mm thickness film-coated tablets.
Formulation
Tablet core
Lactose
Microcrystalline cellulose
Croscarmellose sodium
Sodium laurilsulfate
Magnesium stearate [vegetable]
Film coat
Lactose monohydrate
Hypromellose 2910 (15mPa)
Titanium dioxide (E171)
Triacetin
Apixaban Denk 2.5 mg film-coated tablets contain Iron oxide yellow (E172)
Apixaban Denk 5 mg film-coated tablets contain Iron oxide red (E172)
Summary & Scientific PAR – Generics 7/13Container system PVC/PVdC/aluminium blisters in cartons or HDPE bottles. II.2 2.2 Drug Substance INN: Apixaban Chemical names: 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxamide Chirality: Apixaban does not contain any stereogenic center or any chirality element, consequently it has no isomers. Therefore, Apixaban is an achiral molecule. Manufacturing: Drug substance apixaban is manufactured by the ASMF holder MEDICHEM MANUFACTURING (MALTA) LTD. The manufacturing process has been adequately described and the expected information has been essentially included in the Restricted Part of the ASMF. Specifications: The control tests and specifications for drug substance product are adequately drawn up. Stability studies have been performed with the drug substance. II.3 Medicinal Product The development of the product has been described, the excipients are common pharmacopoeial excipients. They are in accordance with the Ph. Eur. The choice of excipients in adults is justified. The formulation studies are suitable. Principles of quality by design were used, together with design of experiments. Manufacturing process development is acceptable. The product specifications cover appropriate parameters for this dosage form. The proposed limits for maximum single unknown and known impurities are acceptable. Forced degradation studies have been provided. Batch analysis data is presented on four batches per strength. The applicant has conducted a Risk Evaluation as Step 1 concerning the presence of nitrosamine impurities in the medicinal product. The applicant has provided extensive information in response to the questions raised by the RMS. The conditions used in the stability studies are according to the ICH stability guideline. A bulk stability study of twelve months was conducted together with stability studies in extreme conditions. A 48 month shelf life is granted for the bottles while 24 months are granted for the blisters. II.4 Discussion on chemical, pharmaceutical and biological aspects Information on development, manufacture and control of the active substance and finished product has been presented in a satisfactory manner. The results of tests carried out indicate consistency and uniformity of important product quality characteristics, and these in turn lead to the conclusion that the product should have a satisfactory and uniform performance in clinical use. Summary & Scientific PAR – Generics 8/13
III. NON-CLINICAL ASPECTS III.1 Introduction The pharmacological, pharmacokinetic and toxicological properties of apixaban are well known. As apixaban is a well known active substance, no further studies are required and the applicant has provided none. An overview based on a literature review is thus appropriate. III.2 Ecotoxicity/environmental risk assessment (ERA) Since Apixaban Denk 2.5 mg, 5 mg film-coated tablets are intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. III.3 Discussion on the non-clinical aspects The application is made under reference to article 10(1) of Directive 2001/83/EC as amended. Abridged applications avoid the need for repetitive tests on animals and humans. IV. CLINICAL ASPECTS IV.1 Introduction This application for marketing authorisation is based on the Art 10(1) of the 2001/83/EC which allows the generic applicant to reference the clinical and non-clinical data from the originator. A single bioequivalence study was conducted with the 5 mg strength. A biowaiver is requested for the Apixaban 2.5 mg strength, based on the proven bioequivalence of the Apixaban 2.5 mg film-coated tablets and the fulfilment of all requirements of the ‘Guideline on the Investigation of Bioequivalence’ (CPMP/EWP/QWP/1401/98 Rev 1/Corr**). The formulation used in the bioequivalence studies was the same as the to-be-marketed formulation. IV.2 Pharmacokinetics Bioequivalence studies A Phase I bioequivalence trial, open-label, two-period, two-sequence, two-way crossover, block randomised, single dose bioequivalence study to evaluate and compare the bioavailability (BA) and therefore to assess the bioequivalence (BE) between a Test formulation of Apixaban 5 mg film-coated tablets (Test: manufactured by Combino Pharm (Malta) Ltd.) and Eliquis® 5 mg film-coated tablets (MAH: Bristol-Myers Squibb S.r.l (Italy) and sourced from Germany) in healthy adult male subjects under fasting conditions. Summary & Scientific PAR – Generics 9/13
Summary of pharmacokinetic parameters of apixaban 5 mg under fasting conditions (n=24) ANOVA 90% CI (Log transformed) and CV% for pharmacokinetic parameters of apixaban 5 mg (test vs reference) (Fasting, n=24) Conclusion on bioequivalence studies: Based on the submitted bioequivalence study Apixaban Denk 5 mg film-coated tablets is considered bioequivalent with Eliquis® 5 mg film coated tablets. , The results of study 19ANE-3274C with 5 mg formulation can be extrapolated to other strengths 2.5 mg, according to conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section 4.1.6. The justification for BCS (Biopharmaceutics Classification System) - based biowaiver can be accepted. Summary & Scientific PAR – Generics 10/13
IV.3 Risk Management Plan
The MAH has submitted a risk management plan, in accordance with the requirements of Directive
2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to
identify, characterise, prevent or minimise risks relating to Apixaban Denk 2.5 mg and 5 mg film-
coated tablets.
Summary of safety concerns
Important identified risks - Bleeding
Important potential risks - Liver Injury
- Potential risk of bleeding or thrombosis due to
overdose or underdose
Missing information - Use in patients with severe renal impairment
• Pharmacovigilance plan
Since the safety concerns are well characterized, routine pharmacovigilance measures are
deemed sufficient. As current routine pharmacovigilance activities are sufficient, no additional
Pharmacovigilance activities are recommended for apixaban 2.5 mg and 5 mg film-coated
tablets. This is endorsed.
• Plans for post-authorisation efficacy studies
N/A
• Risk minimisation measures
Applicant submitted a summary table of pharmacovigilance activities and risk minimisation
activities by safety concern. The routine and additional risk minimisation measures proposed
are acceptable.
Safety concern Risk minimisation measures Pharmacovigilance activities
Bleeding Routine risk minimisation Routine pharmacovigilance
measures: activities:
SmPC section 4.2 “Posology and • Adverse reactions reporting
method of administration” • Signal detection
Contraindication in SmPC section • PSURs if applicable (EURD)
4.3 “Contraindication”
Warning in SmPC section 4.4 Additional pharmacovigilance
“Special warnings and activities:
precautions for use”
Warning in SmPC section 4.5 This product has additional risk
“Interaction with other medicinal minimisation measures. The
products and other forms of objective of these risk
interactions” minimisation measures is to
• Cyp 3A4 and P-gp inhibitors increase awareness about the
• Anticoagulants potential risk of bleeding during
• NSAIDS/platelet aggregation treatment with Apixaban film-
inhibitors coated tablets and providing
• SSRIs/SNRIs guidance on how to manage that
Haemorrhage is listed in SmPC risk. For this reason, the ultimate
section 4.8 “Undesirable effects” measure of success should be
Summary & Scientific PAR – Generics 11/13SmPC section 4.9 “Overdose” linked to this objective. In case
any bleeding will occur, these
Additional risk Minimisation risk minimisation measures will
measures: be evaluated in order to assess if
they should remain unchanged or
• Prescriber Guide any modifications should be
• Patient Alert Card made. This evaluation will be
performed in the PSURs (if
applicable according to the
EURD) or during signal detection
activity.
Liver Injury Routine risk minimisation Routine pharmacovigilance
measures: activities:
SmPC section 4.2 “Posology and • Adverse reactions reporting
method of administration” • Signal detection
(Hepatic impairment) • PSURs if applicable (EURD)
Contraindication in SmPC section
4.3 “Contraindication”
SmPC section 4.4 “Special
warnings and precautions for use”
SmPC section 4.8 “Undesirable
effects”
Potential risk of Routine risk minimisation Routine pharmacovigilance
bleeding or measures: activities:
thrombosis due to
overdose or SmPC section 4.2 “Posology and • Adverse reactions reporting
underdose method of administration” • Signal detection
SmPC section 4.9 “Overdose” • PSURs if applicable (EURD)
Additional risk minimisation
measures:
• Prescriber Guide
Use in patients with Routine risk minimisation Routine pharmacovigilance
severe renal measures: activities:
impairment
SmPC section 4.2 “Posology and • Adverse reactions reporting
method of administration” • Signal detection
SmPC section 4.4 “Special • PSURs if applicable (EURD)
warnings and precautions for use”
SmPC section 5.2
“Pharmacokinetic properties”
Specific dosing recommendations
are provided in the SmPC for each
indication
- If applicable: Table of Ongoing and Planned Additional Pharmacovigilance Studies / Activities in the
Pharmacovigilance Plan as approved in RMP
Summary & Scientific PAR – Generics 12/13IV.4 Discussion on the clinical aspects
The application is made under reference to article 10(1) of Directive 2001/83/EC as amended.
Abridged applications avoid the need for repetitive tests on animals and humans.
V. USER CONSULTATION
A user consultation with target patient groups on the package information leaflet (PIL) has been
performed on the basis of a bridging report making reference to Eliquis 2.5 mg & 5 mg film-coated
tablets, EMEA/H/C/002148 with regards to content, key messages and safe use.
With regards to design and layout a bridging report with Perindopril/Amlodipine Denk 4 mg/5 mg,
NL/H/4881/001-004/DC. The bridging report submitted by the applicant has been found acceptable.
VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
From a quality point of view the benefit-risk assessment is positive and the application is approvable.
The application contains an adequate review of published non-clinical and clinical data and the
bioequivalence has been shown.
Summary & Scientific PAR – Generics 13/13You can also read
